Multiple electrode lead and a system for deep electrical neurostimulation including such a lead

ABSTRACT

A lead for deep electrical neurostimulation, the lead comprising:
         a rod of biocompatible material; and   a blade, also of biocompatible material, secured to one end of said rod and in alignment therewith;       

     in which said blade presents two main faces and a plurality of electrodes disposed on at least one of said two main faces in a two-dimensional configuration, said electrodes being connected to conductor elements disposed inside or on a surface of said rod. 
     A deep electrical neurostimulation system comprising: an electrical pulse generator for deep electrical neurostimulation; and at least one lead of the above-described type, having its electrodes electrically connected to said electrical pulse generator.

The invention relates to a lead for deep electrical neurostimulation,and more particularly for deep brain electrostimulation. The inventionalso relates to a system for deep electrical neurostimulation andincluding at least one such lead.

BACKGROUND OF THE INVENTION

Deep brain stimulation is a therapeutic technique comprising implantinga medical appliance known as a brain stimulator that serves to sendelectrical pulses to specific regions of the brain. For example,stimulation of the nuclei of the thalamus or of the hypothalamus can beused for treating motor disorders such as tremor, caused in particularby Parkinson's syndrome; in this context, reference can be made to thefollowing articles:

-   P. Krack, P. Pollak, P. Limousin, A. Benzzaous, A. L. Benabid, The    Lancet, Vol. 350, Dec. 6, 1977; and-   A. L. Benadid et al., Acta Neurochirurgica suppl., Vol. 58, pp.    39-44, 1993.

It has also been envisaged to stimulate the posterior hypothalamicnucleus for treating cluster headaches, periaqueductal gray matter forattenuating pain, and the ventromedial hypothalamus for treating certainkinds of obesity; in this respect, reference can be made to thefollowing articles:

-   A. Takaki, S. Aou, Y. Oomura, E. Okada, T. Hori, “Feeding    suppression elicited by electrical and chemical stimulation of    monkey hypothalamus”, Am. J. Physiol. 262 (Regulatory Integrative    Comp. Physiol. 31) R5866-R594, 1992.-   K. Sano, Y. Mayanagi, H. Sekino, M. Ogashiwa, et al., “Results of    stimulation and destruction of the posterior hypothalamus in    man”, J. Neurosurg 33, December 1980, pp. 689-707.-   C. Bielajew, J. Stenger, D. Schindler, “Factors that contribute to    reduce weight gain following chronic ventromedial stimulation”,    Behav. Brain Res. 62 (1994), pp. 143-156.-   F. Brown, R. Fessler, J. Rachlin, S. Mullan, “Changes in food intake    with electrical stimulation of the ventromedial hypothalamus in    dogs”, J. Neurosurg. 60, pp. 1353-1257 (1984).

Recently, a study has shown that electrical stimulation of the subgenualcingulate cortex, and more precisely of Brodmann area 25 (CG25) can beused for treating particularly severe and treatment-resistant forms ofclinical depression [H. S. Mayberg et al., “Deep brain stimulation fortreatment-resistant depression”, Neuron, Vol. 45, pp. 651-660, Mar. 3,2005]. The stimulation method recommended is stimulation of the CG25subgenual cortex by direct application, between the hemispheres, usingelectrodes presenting surfaces similar to those used for stimulatingpremotor cortexes in indications for refractory pain.

In any event, deep brain stimulation involves inserting a flexible leadinto the patient's skull under guidance from a cannula and/or a rigidstylet, until the tip of said lead reaches the region of the brain thatis to be stimulated. Close to its tip, the lead has electrodes(generally four electrodes) that are connected via a subcutaneous cableto a pulse generator appliance that is implanted under the patient'sskin like a conventional cardiac pacemaker. The cannula and/or thestylet are extracted from the patient's skull after being used forinserting the lead, and the lead is then left in place for a durationthat may be as long as several years.

A more detailed description of the procedure for implanting a lead fordeep brain stimulation is given by the following document:“Medtronic—DBS™ lead kit for deep brain stimulation 3387 3389—Implantmanual” from the supplier Medtronic Inc., downloadable from thefollowing Internet site:

http://www.medtronic.com/physician/activa/downloadablefiles/197928_b_(—)006.pdf

Leads for deep electrical neurostimulation of conventional type aredescribed for example in the above-mentioned document from the supplierMedtronic, and also in document U.S. Pat. No. 6,512,958.

The rectilinear shape of the lead is required by the need to makeinsertion thereof as little traumatic as possible for the patient.However, that has the drawback of allowing only a very small region ofbrain tissue to be stimulated, whereas in order to obtain more effectivetreatment it would be desirable to be able to act on a target of largervolume. Implanting a plurality of leads directed at distinct points of acommon target region of relatively large volume is indeed possible, butthat multiplies the risks and the side effects of the surgery.

OBJECTS AND SUMMARY OF THE INVENTION

An object of the invention is thus to provide a lead for deep electricalneurostimulation making it possible, at least in the context of certainapplications, such as stimulating the CG25 region, to obtain moreeffective treatment, while minimizing the risks and the side effects ofsuch treatment.

According to the invention, this object is achieved by a lead for deepelectrical neurostimulation, the lead comprising: a rod of biocompatiblematerial; and a blade, also of biocompatible material, secured to oneend of said rod and in alignment therewith; in which said blade presentstwo main faces and a plurality of electrodes disposed on at least one ofsaid two main faces in a two-dimensional configuration, said electrodesbeing connected to conductor elements disposed inside or on a surface ofsaid rod.

In particular embodiments of the invention:

-   -   Said blade may present a plurality of electrodes disposed on its        two opposite main faces.    -   The number of electrodes placed on said or each main face of        said blade may lie in the range 1 to 40 and preferably in the        range 5 to 20.    -   Said rod may be substantially rectilinear.    -   Said rod and said blade may be made, at least in part, out of a        biocompatible material selected from: silicones; siloxanes;        polyurethane; polyvinyl chloride; benzocyclobutene (BCB);        polyimides; and parylen.    -   Said rod and said blade may be made as a single piece.    -   Said lead may present a total length lying in the range 4        centimeters (cm) to 10 cm, and preferably in the range 5 cm to 8        cm.    -   Said lead may present a substantially planar shape, with a        thickness lying in the range 25 micrometers (μm) to 3        millimeters (mm), and preferably in the range 50 μm to 2 mm.    -   Said main faces of the blade may present an area lying in the        range 10 square millimeters (mm²) to 500 mm², and preferably in        the range 20 mm² to 450 mm².    -   Said blade may present a sickle shape, an elliptical shape, or a        shape that matches the outline of a CG25 zone of a human brain.    -   At least said rod may present a hollow section with a lumen        extending longitudinally therein, in which case said lead may        include a rigid stylet inserted removably within said lumen.    -   Said rod may present, at rest, a shape that is not rectilinear        and that is capable of straightening in reversible manner when        said stylet is inserted therein and of returning to its        non-rectilinear shape when the stylet is withdrawn.    -   Said blade may be hollow and capable of stretching reversibly        during insertion of said stylet so as to be capable of returning        to its original shape when the stylet is withdrawn.    -   Said lead may include longitudinal stiffener beams incorporated        in said rod. Said longitudinal stiffener beams may be made of a        material selected from non-magnetic metals and alloys and carbon        fibers.    -   Said electrodes may present a covering of        electrically-conductive carbon nanotubes, and more particularly        multi-walled nanotubes, preferably with ramifications, covering        silicone pellets fitted onto the surfaces of said electrodes.

The invention also relates to a deep electrical neurostimulation systemcomprising: an electrical pulse generator for deep electricalneurostimulation; and at least one lead as described above, having itselectrodes electrically connected to said electrical pulse generator.

BRIEF DESCRIPTION OF THE DRAWINGS

Other characteristics, details, and advantages of the invention appearon reading the following description made with reference to theaccompanying drawings given by way of example and showing, respectively:

FIG. 1, a plan view of a lead of the invention;

FIG. 2, a longitudinal section view on line II-II of a lead in a firstembodiment of the invention;

FIG. 3, a cross-section view on line of a lead in said first embodimentof the invention;

FIG. 4, a cross-section view of a lead in a second embodiment of theinvention; and

FIG. 5, a diagram showing the principle of a deep electricneurostimulation system including a lead of the invention implanted inthe brain of a patient in order to stimulate the CG25 region of thepatient's subgenual cingulate cortex.

MORE DETAILED DESCRIPTION

The lead 1 of the invention essentially comprises two portions: asubstantially rectilinear rod 10 and a blade 20 in the form of a sickleor kidney bean, secured to a so-called “distal” end of said rod 10 andin alignment therewith, so as to constitute an extension. Both the rod10 and the blade 20 are made of biocompatible material, preferably arelatively flexible material such as silicone, siloxane, polyurethane,polyvinyl chloride, benzocyclobutene (BCB), polyimide, and parylen. Therod 10 and the blade 20 are preferably made as a single piece, but thatis not essential.

The lead 1 presents a structure that is substantially planar. The rod 10presents a section that is at least approximately rectangular, as shownin FIGS. 3 and 4, having thickness E generally lying in the range 25 μmto 3 mm, and preferably lying in the range 50 μm to 2 mm, and a width Lgenerally lying in the range 10 mm to 40 mm, and preferably in the range15 mm to 30 mm. In a variant, the rod 10 may also be substantiallycylindrical in shape, having a radius generally lying in the range 0.5mm to 2 mm. The rod 10 may be situated in the middle of the blade 20 asshown in the figures, or else on one edge thereof, depending on theshape of the zone that is to be stimulated and depending on rigidityconstraints during insertion.

The blade 20 also presents a structure that is substantially planar,having thickness of the same order as magnitude as that of the rod 10,and preferably having the same thickness. The blade presents twoopposite main faces 21 and 22 that, in the example shown in FIGS. 1 and5, are sickle shaped, with an area lying approximately in the range 10mm² to 750 mm², and preferably in the range 100 mm² to 450 mm². Thesickle or kidney bean shape is selected because it correspondsapproximately to the shape of the CG25 area that is to be stimulated. Ina variant, it is possible to select a shape that is more complex,fitting more precisely to the outline of the CG25 area, or conversely ashape that is simpler, being elliptical or circular. Different shapesmay be provided, in particular for stimulating other zones of the brain.In general, it is advantageous for the blade 20 to extend over theentire surface of the zone that is to be stimulated, or even further.

The length LG of the lead 1 preferably lies in the range 3 cm to 8 cm.This length must be sufficient to reach the target tissue forstimulation, e.g. the CG25 region of the human brain, withoutexcessively projecting beyond the surface of the patient's body.

Electrodes 31, 32 project from the two opposite main faces 21 and 22 ofthe blade 20. These electrodes are made of a biocompatible conductivematerial such as platinum and they are disposed in a two-dimensionalconfiguration. By way of example, FIG. 1 shows a lead 1 in which theblade 20 presents nine electrodes on each of its main faces, theelectrodes being disposed in a pattern that enables the CG25 area to bestimulated approximately uniformly. The number of electrodes on eachmain face 21, 22 may for example lie in the range 1 to 40, andpreferably in the range 5 to 20.

The dimensions of the electrodes 31, 32 are determined as a function ofthe intended stimulation current, it being understood that it is notdesirable to exceed a charge density of 30 micro coulombs per squarecentimeter (μC/cm²) per pulse.

In a variant, only one of the main faces of the blade 20 needs beprovided with electrodes, so that the target tissue is electricallystimulated only unilaterally. Bilateral electrostimulation can also beobtained by making use of two leads of this type placed back to back.

The electrodes 31, 32 are connected to conductor elements 33 that extendlongitudinally along the rod 10 as far as external electrical contacts34 situated at the so-called “proximal” end of the rod, remote from theblade 20. As shown in FIG. 5, when the lead 1 is implanted in the brainCV of a patient, the external electrical contacts project outside thecranium CR, and enable the electrodes 31, 32 to be electricallyconnected to an electrical pulse generator 100 for deep electricalneurostimulation via a subcutaneous cable 200.

The conductor elements 33 may be disposed inside the rod 10 or on itssurface; however, if they are on the surface they must be covered in alayer that is electrically insulating and passivating.

The lead 1 of the invention, and in particular its rod 10, must besufficiently flexible to avoid giving rise to internal lesions when itis permanently implanted, e.g. in the brain of a patient.Simultaneously, in order to be inserted it must present sufficientstiffness.

In known manner, these contradictory requirements are solved by using alead 1, or at least a rod 10, that presents a hollow section with alongitudinal lumen 11 in which it is possible to insert removably astiffener stylet 40 that is designed to be extracted from the lead 1after it has been introduced into the body of a patient.

In a variant of the invention, the rod 10 may be preformed to present anon-rectilinear shape. Such a rod straightens out reversibly when thestylet 40 is inserted, thus making it easier to implant; thereafter,when the stylet is withdrawn it returns to its original non-rectilinearshape. This makes it possible to reach zones of the brain that wouldotherwise be difficult to access, and minimizes lesions to theparenchyma caused by inserting the lead.

It is also possible to make a lead presenting a blade 20 that is hollowand that preferably includes longitudinal notches. When the stylet 40bears against the distal end of the lead, such a blade stretches,becoming longer and narrower. The lead then becomes almost rectilinearin shape, thereby minimizing the size of the incision that needs to bemade in the cranium in order to insert it, and also minimizing lesionsto the parenchyma caused by said insertion. When the stylet iswithdrawn, the blade 20 returns to its original shape in order tostimulate the target region of the brain effectively.

Cerebral stimulation leads of shape that is temporarily modified byinserting a stiffener stylet are described in greater detail in patentapplication FR 07/01353 filed on Feb. 26, 2007 by the present Applicant.

In some circumstances, it can be preferable to use a lead 1 that isitself provided with a certain amount of stiffness, but that has acovering that is relatively flexible. This can be achieved by stiffeninga lead that is made mainly out of flexible material by incorporatinglongitudinal beams 50, e.g. made of tantalum or of titanium, or of anyother metal that is biocompatible and compatible with magnetic resonanceimaging (MRI), or out of carbon fibers. The beams 50 are preferably faraway from the bending axis of the rod 10, which amounts to increasingthe stiffness of the beams for given volume.

In the embodiment of FIG. 4, the beams 50 stiffen the lead 1sufficiently to enable it to be inserted without a stylet 40 beingnecessary; consequently, the lead has a solid section, without anylumen. It is also possible to envisage an intermediate embodiment inwhich the beams 50 do not provide sufficient stiffness, with a removablestylet 40 being used for inserting the lead, as in the embodiment ofFIG. 3.

From a technical point of view, leads of the invention can be obtainedusing various fabrication methods.

For leads having a thickness greater than 100 μm and up to a fewmillimeters, in order to fabricate the electrodes 31, 32, the conductorelements 33, and the external electrical contacts 34, it is preferableto use steps of photolithography and of etching a metal on an elastomerof the siloxane type, or steps of depositing conductive inks bydepositing nanopowders, followed by a laser sintering operation thatenables good electrical conduction to be achieved, these steps beingfollowed by passivation with photosensitive silicone or parylen locallyopened by plasma or laser etching.

For leads of thickness lying in the range 10 μm to 100 μm approximately,the starting material is an optionally photosensitive polymer (shapeobtained by lithography or by plasma etching), such as a polyimide orbenzocyclobutene (BCB), deposited by centrifuging, and havingtwo-dimensional conductor patterns thereon constituting the electrodes31, 32, the conductor elements 33, and the external electrical contacts34 which patterns are made by photolithography or likewise by depositingconductive inks or by depositing nanopowders. The first method(lithography) enables resolutions to be achieved that are of micrometerorder, whereas the other methods are restricted to patterns greater than10 μm. Passivation is obtained by depositing a second layer of the samepolymer. A hollow section can be obtained using sacrificial layers, asdescribed in the article by Kee Keun Lee, Jiping He, Ryan, Clement,Stephen Massia, and Bruce Kim, published in the journal “Biosensors andbioelectronics”, No. 20, pp. 404 to 407, 2004, or else by sealing afterphoto-polymerization. It is with such extremely fine leads that it isthe most advantageous to make use of reinforcing beams 50.

In any event, the conductor elements 33 can be made of metal, indium andtin oxide (ITO), or graphite, and they may be textured by methodsderived from semiconductor or printed circuit technology.

In order to increase the biocompatibility of the stimulation and/orrecording electrodes, it is possible to add thin silicon pellets coatedin carbon nanotubes. The electrical properties of carbon nanotubes(multiple walls, with or without ramification) produce a verysignificant increase in the signal-to-noise ratio by reducing theimpedance of the electrode (which property is associated with increasingits developed surface area). Such performance is desirable for anelectrode that records cortical activity in the stimulation zone like anelectrocorticogram (analogous to an electroencephalogram, but made onthe cortex).

In stimulation, electrodes including carbon nanotubes also presentadvantages. The electrochemical characterizations of such electrodesshow that the quantity of charge that can be injected is much greaterthan that from a titanium nitride electrode or a platinum electrode(e.g. characterization performed by CEA/Leti: where the capacitance perunit area of electrodes with carbon nanotubes has been measured at1.3×10⁻² farads per square centimeter (F/cm²) as compared with 5.10×10⁻⁴F/cm² for the same electrodes without nanotubes. The use of carbonnanotubes thus provides a significant advantage for stimulationelectrodes. In addition, document U.S. Pat. No. 7,162,308 describes theadvantages of growing carbon nanotubes out of biocompatibility material.

The use of a lead of the invention to treat certain forms of clinicaldepression is illustrated in FIG. 5. In these forms of depression,region 25 of the subgenual cingulate cortex, CG25, is hyperactive, andthis hyperactivity can be moderated by chronic electrical stimulation.Each hemisphere of the brain CV has its own CG25 region, adjacent to thelongitudinal fissure of the cerebrium (coronal section plane of thefigure). In general, it is desirable to stimulate the regions in bothhemispheres, however unilateral stimulation may be preferred in certainspecial circumstances.

A lead 1 of the invention can be inserted into the skull of a patientvia an opening of appropriate shape made through the cranium CR, theblade 20 sliding in the plane of the longitudinal fissure.

More precisely, the patient is positioned on a stereotaxic frame, astereotaxic robot also being positioned on said frame to determine onthe scalp the site for the cutaneous incision, and the center of theright parasagittal trepan that is to be made to approach thelongitudinal fissure of the cerebrum, under an operating microscope.Thereafter, a cutaneous incision is made parallel to the corona suture,thus making it more attractive than a parasagittal incision, which wouldrun the risk of projecting too far beyond the hair line. With the scalpretracted, craniotomy is performed using a trepan having a diameter of 3cm or 5 cm, on the non-dominant side of the patient, thus generally onthe right-hand side if the patient is right-handed, tangentially to themidline. The dura-mater is incised along a diameter parallel to themidline, and two radial slits are formed towards the midline so as tolead to the longitudinal fissure of the cerebrium. This is carefullyseparated from the falx of cerebrum by sectioning adhesions of thearachnoidea to the level of the base of the anterior stage, goingtowards the most posterior, subgenual portion of the medio-basal frontalcortex. The stereotaxic installation makes it possible to performradiological monitoring during the operation to ensure that positioningis correct relative to the determined target.

Thereafter, the lead 1 is advanced inside said longitudinal fissure,where appropriate with the help of a stiffener stylet 40, until theblade 20 carrying the electrodes 31, 32 reaches the CG25 region that isto be stimulated. After the stylet 40 has been withdrawn, X-rayinspection is performed and the dura-mater is sutured, the piece of boneis put back into place and secured to the scalp by non-resorbablestitches, allowing the cable to the electrodes to extend outwards viathe saw cut of the trepan. The distal ends are left under the periosteumin the same manner as for intra-parenchyme electrodes.

On the third day after implanting the electrodes, a new MRI is performedto monitor the positions of the electrodes and to verify that there areno bleeding complications.

Under general anesthesia, six days after implantation, an electricalpulse generator 100 for deep electrical neurostimulation is implantedunder the skin of the patient in the right subclavicular region, and isconnected to the external electrical contacts 34 of the lead via adouble extender 200 running from the head to the collar bone throughsuccessive cutaneous tunnels.

In a variant, two leads 1, each having electrodes on only one main faceof the blade 20, may be placed back to back and connected to the samepulse generator 100, or to two individual generators.

Although the invention is described above with reference to its use fortreating clinical depression by stimulating region 25 of the subgenualcingulate cortex (CG25), the invention can be applied more generally todeep electrical neurostimulation of other regions of the brain, orindeed of other tissues, such as the spinal cord.

1-20. (canceled)
 21. A lead for deep electrical neurostimulation, thelead comprising: a rod of biocompatible material, having a stiffnesswhich is sufficient for allowing its insertion into a brain of apatient, wherein said rod presents a hollow section with a lumenextending longitudinally therein; a rigid stylet inserted removablywithin said lumen in order to make said rod stiff enough to allowinsertion of the lead into a brain of a patient; and a blade, also ofbiocompatible material, secured to one end of said rod and in alignmenttherewith; in which said blade presents two main faces and a pluralityof electrodes disposed on at least one of said two main faces in atwo-dimensional configuration, said electrodes being connected toconductor elements disposed inside or on a surface of said rod; whereinsaid blade is hollow and capable of stretching reversibly duringinsertion of said stylet so as to be capable of returning to itsoriginal shape when the stylet is withdrawn.
 22. A lead according toclaim 21, in which said blade presents a plurality of electrodesdisposed on its two opposite main faces.
 23. A lead according to claim21, in which the number of electrodes placed on said or each main faceof said blade lies in the range 1 to
 40. 24. A lead according to claim21, in which said rod is substantially rectilinear.
 25. A lead accordingto claim 21, in which said rod and said blade are made, at least inpart, out of a biocompatible material selected from: silicones;siloxanes; polyurethane; polyvinyl chloride; benzocyclobutene;polyimides; and parylen.
 26. A lead according to claim 21, in which saidrod and said blade are made as a single piece.
 27. A lead according toclaim 21, presenting a total length lying in the range 4 cm to 10 cm.28. A lead according to claim 21, presenting a substantially planarshape, with a thickness lying in the range 25 μm to 3 mm.
 29. A leadaccording to claim 21, in which said main faces of the blade present anarea lying in the range 10 mm² to 500 mm².
 30. A lead according to claim21, in which said blade presents a sickle shape, an elliptical shape, ora shape that matches the outline of a CG25 zone of a human brain.
 31. Alead according to claim 21, including longitudinal stiffener beamsincorporated in said rod.
 32. A lead according to claim 35, in whichsaid longitudinal stiffener beams are made of a material selected fromnon-magnetic metals and alloys and carbon fibers.
 33. A lead accordingto claim 21, in which said electrodes present a covering ofelectrically-conductive carbon nanotubes.
 34. A lead according to claim33, in which said carbon nanotubes are multi-wall nanotubes coveringpellets of silicon fitted onto the surface of said electrodes.
 35. Adeep electrical neurostimulation system comprising: an electrical pulsegenerator for deep electrical neurostimulation; and at least one leadfor deep electrical neurostimulation, having its electrodes electricallyconnected to said electrical pulse generator, wherein the leadcomprises: a rod of biocompatible material, having a stiffness which issufficient for allowing its insertion into a brain of a patient, whereinsaid rod presents a hollow section with a lumen extending longitudinallytherein; a rigid stylet inserted removably within said lumen in order tomake said rod stiff enough to allow insertion of the lead into a brainof a patient; and a blade, also of biocompatible material, secured toone end of said rod and in alignment therewith; wherein said bladepresents two main faces and a plurality of electrodes disposed on atleast one of said two main faces in a two-dimensional configuration,said electrodes being connected to conductor elements disposed inside oron a surface of said rod; and wherein said blade is hollow and capableof stretching reversibly during insertion of said stylet so as to becapable of returning to its original shape when the stylet is withdrawn.36. A deep electrical neurostimulation system according to claim 35,wherein said electrical pulse generator is configured to generateelectrical impulsion adapted for treating clinical depression bystimulating a CG25 zone of a human brain.